Control of the fibrinolytic system has been considered an important therapeutic goal because of the number of human disease states which could then be treated or prevented. For example, myocardial infarction, deep vein thrombosis, and pulmonary embolism all appear to involve undesirable fibrin clot formation. While many proteins interact in complex ways in fibrinolysis, some success in the treatment of myocardial infarction has been attained by use of various proteins termed plasminogen activators. It is known that the use of tissue plasminogen activators, prourokinase, urokinase itself and various second generation plasminogen activators derived from t-PA and prourokinase may be useful in the treatment of the body to obtain a thrombolytic effect in vivo.
As used in these specifications and claims, t-PA type plasminogen activator is meant to include and mean plasminogen activator of the tissue type known as (t-PA) as well as various derivatives thereof which plasminogen activator may occur naturally, or be derived by genetic engineering means. Similarly prourokinase type plasminogen activators are meant to include single chain prourokinase (scu-PA) itself and various second generation derivatives thereof having plasminogen activation properties as is known in the literature and will be described herein.
Such t-PA type or tissue type plasminoqen activators are well known in the literature as are prourokinase type plasminogen activators as for example described in European Patent Application publication number 0,223,192 and referred to in said application.
It is pointed out in that application that t-PA is a well known tissue type plasminogen activator. Prourokinase is referred to therein as scu-PA and is a single chain form of urokinase type plasminogen activator.
The patent application suggests a synerqistic effect when using t-PA in combination with prourokinase or urokinase type plasminogen activator. The synergistic effect obtained was found to be desirable in certain examples given.
Another known plasminogen activator of a wholly different type than t-PA and scu-PA is streptokinase. Streptokinase for some time had been the most widely used thrombolytic agent for myocardial infarction probably because it has been easier to obtain and far less expensive than tissue plasminogen activator type and prourokinase type plasminogen activators. Streptokinase is known as a nonenzyme protein produced by Lancefield group C strains of beta-hemolytic streptococci. It activates the fibrinolytic system indirectly by complexing with plasminogen to produce a modified plasminogen moiety. For purposes of this invention streptokinase activator as used herein is meant to include streptokinase itself as well as streptokinase plasminogen complexes.